Fine-mapping genomic loci refines bipolar disorder risk genes.

Bipolar disorder (BD) is a heritable mental illness with complex etiology. While the largest published genome-wide association study identified 64 BD risk loci, the causal SNPs and genes within these loci remain unknown. We applied a suite of statistical and functional fine-mapping methods to these loci, and prioritized 22 likely causal SNPs for BD. We mapped these SNPs to genes, and investigated their likely functional consequences by integrating variant annotations, brain cell-type epigenomic annotations, brain quantitative trait loci, and results from rare variant exome sequencing in BD. Convergent lines of evidence supported the roles of SCN2A, TRANK1, DCLK3, INSYN2B, SYNE1, THSD7A, CACNA1B, TUBBP5, PLCB3, PRDX5, KCNK4, AP001453.3, TRPT1, FKBP2, DNAJC4, RASGRP1, FURIN, FES, YWHAE, DPH1, GSDMB, MED24, THRA, EEF1A2, and KCNQ2 in BD. These represent promising candidates for functional experiments to understand biological mechanisms and therapeutic potential. Additionally, we demonstrated that fine-mapping effect sizes can improve performance and transferability of BD polygenic risk scores across ancestrally diverse populations, and present a high-throughput fine-mapping pipeline (https://github.com/mkoromina/SAFFARI).

Neurogenetic and multi-omic sources of overlap among sensation seeking, alcohol consumption, and alcohol use disorder.

Sensation seeking is bidirectionally associated with levels of alcohol consumption in both adult and adolescent samples, and shared neurobiological and genetic influences may in part explain these associations. Links between sensation seeking and alcohol use disorder (AUD) may primarily manifest via increased alcohol consumption rather than through direct effects on increasing problems and consequences. Here the overlap among sensation seeking, alcohol consumption, and AUD was examined using multivariate modelling approaches for genome-wide association study (GWAS) summary statistics in conjunction with neurobiologically informed analyses at multiple levels of investigation. Meta-analytic and genomic structural equation modelling (GenomicSEM) approaches were used to conduct GWAS of sensation seeking, alcohol consumption, and AUD. Resulting summary statistics were used in downstream analyses to examine shared brain tissue enrichment of heritability and genome-wide evidence of overlap (e.g., stratified GenomicSEM, RRHO, genetic correlations with neuroimaging phenotypes), and to identify genomic regions likely contributing to observed genetic overlap across traits (e.g., H-MAGMA and LAVA). Across approaches, results supported shared neurogenetic architecture between sensation seeking and alcohol consumption characterised by overlapping enrichment of genes expressed in midbrain and striatal tissues and variants associated with increased cortical surface area. Alcohol consumption and AUD evidenced overlap in relation to variants associated with decreased frontocortical thickness. Finally, genetic mediation models provided evidence of alcohol consumption mediating associations between sensation seeking and AUD. This study extends previous research by examining critical sources of neurogenetic and multi-omic overlap among sensation seeking, alcohol consumption, and AUD which may underlie observed phenotypic associations.

Predicting first use of heroin from prescription opioid use subtypes: Insights from the Monitoring the Future longitudinal panel.

BACKGROUND: Only a small proportion of individuals who initiate nonmedical use of prescription opioids (NUPO) transition to heroin, suggesting that more nuanced aspects of NUPO may be better indicators of risk for escalating opioid use trajectories. This study leveraged panel data to identify NUPO typologies based on NUPO characteristics associated with opioid risk trajectories (route of administration, motives) and compared rates of heroin initiation at follow-up across typologies. METHODS: Latent class analyses were run among respondents with no history of heroin use from the Monitoring the Future Panel Study (base year N=10,408) at modal ages 18, 19/20, 21/22, 23/24, and 25/26. Indicators included oral NUPO, nonoral NUPO, and NUPO motives to experiment, have a good time with friends, get high, escape problems, manage pain, relax, and sleep. Heroin initiation at follow-ups through modal age 29/30 was predicted from class membership. RESULTS: No NUPO, self-medication (oral, manage pain), recreational (oral, nonoral, experiment, get high, have a good time with friends), and mixed-motive (all routes, all motives) classes emerged. Heroin initiation rates did not differ across no NUPO and self-medication classes; recreational and mixed-motives classes initiated heroin at higher rates than the other classes and comparable rates to each other. Non-NUPO drug use prior to heroin initiation was prevalent in recreational and mixed-motive classes. CONCLUSIONS: NUPO does not uniformly or uniquely increase risk for heroin initiation. Leveraging more nuanced indicators of risk for heroin use and targeting polysubstance use in addition to opioid-specific programming may enhance the efficacy of public health efforts.

Genetic and shared environmental factors explain the association between adolescent polysubstance use and high school noncompletion.

OBJECTIVE: Examine the nature of the relationship between adolescent polysubstance use and high school noncompletion. METHOD: Among a sample of 9,579 adult Australian twins (58.63% female, Mage = 30.59), we examined the association between the number of substances used in adolescence and high school noncompletion within a discordant twin design and bivariate twin analysis. RESULTS: In individual-level models controlling for parental education, conduct disorder symptoms, childhood major depression, sex, zygosity, and cohort, each additional substance used in adolescence was associated with a 30% increase in the odds of high school noncompletion (OR = 1.30 [1.18, 1.42]). Discordant twin models found that the potentially causal effect of adolescent use on high school noncompletion was nonsignificant (OR = 1.19 [0.96, 1.47]). Follow-up bivariate twin models suggested genetic (35.4%, 95% CI [24.5%, 48.7%]) and shared environmental influences (27.8%, 95% CI [12.7%, 35.1%]) each contributed to the covariation in adolescent polysubstance use and early school dropout. CONCLUSIONS: The association between polysubstance use and early school dropout was largely accounted for by genetic and shared environmental factors, with nonsignificant evidence for a potentially causal association. Future research should examine whether underlying shared risk factors reflect a general propensity for addiction, a broader externalizing liability, or a combination of the two. More evidence using finer measurement of substance use is needed to rule out a causal association between adolescent polysubstance use and high school noncompletion. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Dual-systems models of the genetic architecture of impulsive personality traits: neurogenetic evidence of distinct but related factors.

BACKGROUND: Dual-systems models, positing an interaction between two distinct and competing systems (i.e. top-down self-control, and bottom-up reward- or emotion-based drive), provide a parsimonious framework for investigating the interplay between cortical and subcortical brain regions relevant to impulsive personality traits (IPTs) and their associations with psychopathology. Despite recent developments in multivariate analysis of genome-wide association studies (GWAS), molecular genetic investigations of these models have not been conducted. METHODS: Using IPT GWAS, we conducted confirmatory genomic structural equation models (GenomicSEM) to empirically evaluate dual-systems models of the genetic architecture of IPTs. Genetic correlations between dual-systems factors and relevant cortical and subcortical neuroimaging phenotypes (regional/structural volume, cortical surface area, cortical thickness) were estimated and compared. RESULTS: GenomicSEM dual-systems models underscored important sources of shared and unique genetic variance between top-down and bottom-up constructs. Specifically, a dual-systems genomic model consisting of sensation seeking and lack of self-control factors demonstrated distinct but related sources of genetic influences (rg = 0.60). Genetic correlation analyses provided evidence of differential associations between dual-systems factors and cortical neuroimaging phenotypes (e.g. lack of self-control negatively associated with cortical thickness, sensation seeking positively associated with cortical surface area). No significant associations were observed with subcortical phenotypes. CONCLUSIONS: Dual-systems models of the genetic architecture of IPTs tested were consistent with study hypotheses, but associations with relevant neuroimaging phenotypes were mixed (e.g. no associations with subcortical volumes). Findings demonstrate the utility of dual-systems models for studying IPT genetic influences, but also highlight potential limitations as a framework for interpreting IPTs as endophenotypes for psychopathology.

Neurogenetic and multi-omic sources of overlap among sensation seeking, alcohol consumption, and alcohol use disorder.

Sensation seeking is bidirectionally associated with levels of alcohol consumption in both adult and adolescent samples and shared neurobiological and genetic influences may in part explain this association. Links between sensation seeking and alcohol use disorder (AUD) may primarily manifest via increased alcohol consumption rather than through direct effects on increasing problems and consequences. Here the overlap between sensation seeking, alcohol consumption, and AUD was examined using multivariate modeling approaches for genome-wide association study (GWAS) summary statistics in conjunction with neurobiologically-informed analyses at multiple levels of investigation. Meta-analytic and genomic structural equation modeling (GenomicSEM) approaches were used to conduct GWAS of sensation seeking, alcohol consumption, and AUD. Resulting summary statistics were used in downstream analyses to examine shared brain tissue enrichment of heritability and genome-wide evidence of overlap (e.g., stratified GenomicSEM, RRHO, genetic correlations with neuroimaging phenotypes) and to identify genomic regions likely contributing to observed genetic overlap across traits (e.g., HMAGMA, LAVA). Across approaches, results supported shared neurogenetic architecture between sensation seeking and alcohol consumption characterized by overlapping enrichment of genes expressed in midbrain and striatal tissues and variants associated with increased cortical surface area. Alcohol consumption and AUD evidenced overlap in relation to variants associated with decreased frontocortical thickness. Finally, genetic mediation models provided evidence of alcohol consumption mediating associations between sensation seeking and AUD. This study extends previous research by examining critical sources of neurogenetic and multi-omic overlap among sensation seeking, alcohol consumption, and AUD which may underlie observed phenotypic associations.

Specificity in genetic and environmental risk for prescription opioid misuse and heroin use.

BACKGROUND: Many studies aggregate prescription opioid misuse (POM) and heroin use into a single phenotype, but emerging evidence suggests that their genetic and environmental influences may be partially distinct. METHODS: In total, 7164 individual twins (84.12% complete pairs; 59.81% female; mean age = 30.58 years) from the Australian Twin Registry reported their lifetime misuse of prescription opioids, stimulants, and sedatives, and lifetime use of heroin, cannabis, cocaine/crack, illicit stimulants, hallucinogens, inhalants, solvents, and dissociatives via telephone interview. Independent pathway models (IPMs) and common pathway models (CPMs) partitioned the variance of drug use phenotypes into general and drug-specific genetic (a), common environmental (c), and unique environmental factors (e). RESULTS: An IPM with one general a and one general e factor and a one-factor CPM provided comparable fit to the data. General factors accounted for 55% (a = 14%, e = 41%) and 79% (a = 64%, e = 15%) of the respective variation in POM and heroin use in the IPM, and 25% (a = 12%, c = 8%, e = 5%) and 80% (a = 38%, c = 27%, e = 15%) of the respective variation in POM and heroin use in the CPM. Across both models, POM emerged with substantial drug-specific genetic influence (26-39% of total phenotypic variance; 69-74% of genetic variance); heroin use did not (0% of total phenotypic variance; 0% of genetic variance in both models). Prescription sedative misuse also demonstrated significant drug-specific genetic variance. CONCLUSIONS: Genetic variation in POM, but not heroin use, is predominantly drug-specific. Misuse of prescription medications that reduce experiences of subjective distress may be partially influenced by sources of genetic variation separate from illicit drug use.

Dual-systems models of the genetic architecture of impulsive personality traits: Neurogenetic evidence of distinct but related factors.

Background: Dual-systems models provide a parsimonious framework for understanding the interplay between cortical and subcortical brain regions relevant to impulsive personality traits (IPTs) and their associations with psychiatric disorders. Despite recent developments in multivariate analysis of genome-wide association studies (GWAS), molecular genetic investigations of these models have not been conducted. Methods: Using extant IPT GWAS, we conducted confirmatory genomic structural equation models (GenomicSEM) to empirically evaluate dual-systems models of the genetic architecture of IPTs. Genetic correlations between results of multivariate GWAS of dual-systems factors and GWAS of relevant cortical and subcortical neuroimaging phenotypes (regional/structural volume, cortical surface area, cortical thickness) were calculated and compared. Results: Evaluation of GenomicSEM model fit indices for dual-systems models suggested that these models highlight important sources of shared and unique genetic variance between top-down and bottom-up constructs. Specifically, a dual-systems genomic model consisting of sensation seeking and lack of self-control factors demonstrated distinct but related sources of genetic influences ( r g =.60). Genetic correlation analyses provided evidence of differential associations between dual-systems factors and cortical neuroimaging phenotypes (e.g., lack of self-control negatively associated with cortical thickness, sensation seeking positively associated with cortical surface area). However, no significant associations were observed for subcortical phenotypes inconsistent with hypothesized functional localization of dual-systems constructs. Conclusions: Dual-systems models of the genetic architecture of IPTs tested here demonstrate evidence of shared and unique genetic influences and associations with relevant neuroimaging phenotypes. These findings emphasize potential advantages in utilizing dual-systems models to study genetic influences for IPTs and transdiagnostic associations with psychiatric disorders.

Adolescent substance use and high school noncompletion: exploring the nature of the relationship using a discordant twin design.

BACKGROUND AND AIMS: Previous studies have demonstrated associations between substance use and reduced educational attainment; however, many were unable to account for potential confounding factors like genetics and the rearing environment. In the few studies that controlled for these factors, the substances assessed were limited to alcohol, cannabis, and tobacco. To address these limitations, we examined the relationship between adolescent use of seven kinds of substances, the number of additional substances used, and high school noncompletion within a large sample of Australian twins. DESIGN: A series of two-level generalized mixed effects logistic regressions were conducted to examine associations between adolescent substance use and high school noncompletion. SETTING: Australia. PARTICIPANTS: A total of 9579 adult Australian twins from two cohorts of the Australian Twin Registry. MEASUREMENTS: Assessments of high school completion, childhood major depression, conduct disorder symptoms, substance use initiation, demographics, and parental educational attainment using the Australian version of the Semi-Structured Assessment for the Genetics of Alcoholism. FINDINGS: There were unique within-twin-pair effects of use of sedatives (odds ratio [OR] = 22.39 [95% confidence interval (CI) = 1.18-423.48]) and inhalants/solvents (OR = 10.46 [95% CI = 1.30-84.16]) on high school noncompletion. The number of substances used in adolescence was strongly associated with high school noncompletion across all discordant twin models (ORs from 1.50-2.32, Ps < 0.03). CONCLUSIONS: In Australia, adolescent substance use appears to be associated with early school dropout, with the effects of any given substance largely because of the confounding factors of parental education, childhood conduct disorder symptoms, and use of other substances. Sedatives and inhalants/solvents have effects on high school noncompletion that cannot be explained by polysubstance use or familial factors.

Association of Predicted Expression and Multimodel Association Analysis of Substance Abuse Traits.

Introduction: Genome-wide association studies (GWAS) have played a critical role in identifying many thousands of loci associated with complex phenotypes and diseases. This has led to several translations of novel disease susceptibility genes into drug targets and care. This however has not been the case for analyses where sample sizes are small, which suffer from multiple comparisons testing. The present study examined the statistical impact of combining a burden test methodology, PrediXcan, with a multimodel meta-analysis, cross phenotype association (CPASSOC). Methods: The analysis was conducted on 5 addiction traits: family alcoholism, cannabis craving, alcohol, nicotine, and cannabis dependence and 10 brain tissues: anterior cingulate cortex BA24, cerebellar hemisphere, cortex, hippocampus, nucleus accumbens basal ganglia, caudate basal ganglia, cerebellum, frontal cortex BA9, hypothalamus, and putamen basal ganglia. Our sample consisted of 1,640 participants from the University of California, San Francisco (UCSF) Family Alcoholism Study. Genotypes were obtained through low pass whole genome sequencing and the use of Thunder, a linkage disequilibrium variant caller. Results: The post-PrediXcan, gene-phenotype association without aggregation resulted in 2 significant results, HCG27 and SPPL2B. Aggregating across phenotypes resulted no significant findings. Aggregating across tissues resulted in 15 significant and 5 suggestive associations: PPIE, RPL36AL, FOXN2, MTERF4, SEPTIN2, CIAO3, RPL36AL, ZNF304, CCDC66, SSPOP, SLC7A9, LY75, MTRF1L, COA5, and RRP7A; RPS23, GNMT, ERV3-1, APIP, and HLA-B, respectively. Discussion: Given the relatively small size of the cohort, this multimodel approach was able to find over a dozen significant associations between predicted gene expression and addiction traits. Of our findings, 8 had prior associations with similar phenotypes through investigation of the GWAS Atlas. With the onset of improved transcriptome data, this approach should increase in efficacy.

Educational Attainment Polygenic Scores: Examining Evidence for Gene-Environment Interplay with Adolescent Alcohol, Tobacco and Cannabis Use.

Genes associated with educational attainment may be related to or interact with adolescent alcohol, tobacco and cannabis use. Potential gene-environment interplay between educational attainment polygenic scores (EA-PGS) and adolescent alcohol, tobacco, and cannabis use was evaluated with a series of regression models fitted to data from a sample of 1871 adult Australian twins. All models controlled for age, age2, cohort, sex and genetic ancestry as fixed effects, and a genetic relatedness matrix was included as a random effect. Although there was no evidence that adolescent alcohol, tobacco or cannabis use interacted with EA-PGS to influence educational attainment, there was a significant, positive gene-environment correlation with adolescent alcohol use at all PGS thresholds (ps <.02). Higher EA-PGS were associated with an increased likelihood of using alcohol as an adolescent (ΔR2 ranged from 0.5% to 1.1%). The positive gene-environment correlation suggests a complex relationship between educational attainment and alcohol use that is due to common genetic factors.

Contextualizing prescription opioid misuse and heroin use within dimensional models of drug involvement.

Background: Prescription opioid misuse (POM) is often implicated in heroin initiation, despite evidence that POM does not predict heroin initiation any better than other drug use. Additionally, prescription misuse and illicit use behaviors tend to respectively "cluster" together. This study aimed to test a series of theory-driven factor models to explore how POM and heroin use are situated within the broader constellation of drug use that typically occurs alongside opioid (mis)use. Methods: 36,309 individuals from NESARC-III (56.31% female; mean age=45.63 [SD=17.53]) reported their lifetime (mis)use of prescription opioids, prescription stimulants, prescription sedatives, heroin, cannabis, cocaine/crack, illicit stimulants (e.g., methamphetamine), club drugs, hallucinogens, and inhalants, and were administered a DSM-5 substance use disorder (SUD) assessment. Bifactor, correlated factors, and one-factor confirmatory factor models were fit using all drug use/SUD variables and subsequently compared. Results: POM was most strongly correlated with prescription sedative misuse; heroin use was most strongly correlated with cocaine/crack use. All factor models fit the data well. Highly correlated factors and patterns of factor loadings suggested that POM and heroin use were most parsimoniously captured within a general factor alongside all other forms of drug use. This was also the case for SUD. Additional analyses testing an alternate factor structure provided further support for unidimensionality. Conclusions: POM and heroin use, as well as prescription- and heroin-based SUDs, were neither separable nor distinctly associated. Future research should account for other drug use more comprehensively rather than isolating POM as a primary risk factor in heroin use and use disorder.

Predicting disordered gambling across adolescence and young adulthood from polygenic contributions to Big 5 personality traits in a UK birth cohort.

BACKGROUND AND AIMS: Previous research has demonstrated phenotypical associations between disordered gambling (DG) and Big 5 personality traits, and a twin study suggested that shared genetic influences accounted for a substantial portion of this relation. The present study examined associations between DG and polygenic scores (PSs) for Big 5 traits to measure the shared genetic underpinnings of Big 5 personality traits and DG. DESIGN: Zero-inflated negative binomial regression models estimated associations between Big 5 PSs and past-year and life-time assessments of DG in a longitudinally assessed population-based birth cohort. SETTING: United Kingdom. PARTICIPANTS: A total of 4729 unrelated children of European ancestry from the Avon Longitudinal Study of Parents and Children (ALSPAC) with both phenotypical and genetic data. MEASUREMENTS: Phenotypical outcomes included past-year assessment of DG using the problem gambling severity index (PGSI) and life-time assessment of DSM-IV pathological gambling symptoms (DPG) across the ages of 17, 20 and 24 years. Polygenic scores were derived for the Big 5 personality traits of agreeableness, extraversion, conscientiousness, openness and neuroticism using summary statistics from genome-wide association studies (GWAS). FINDINGS: PSs for agreeableness [ß= - 0.25, standard error (SE) = 0.054, P = 3.031e-6, ΔR2 = 0.008] and neuroticism (ß=0.14, SE = 0.046, P = 0.0017, ΔR2 = 0.002) significantly predicted PGSI scores over and above included covariates (i.e. sex and first five ancestral principal components). PSs for agreeableness (ß= - 0.20, SE = 0.056, P = 0.00036, ΔR2 = 0.003) and neuroticism, when interactions with age were taken into account (ß = 0.29, SE = 0.090, P = 0.002, ΔR2 = 0.004), also predicted DPG scores. CONCLUSIONS: Polygenic contributions to low agreeableness and high neuroticism appear to predict two measures of disordered gambling (problem gambling severity index and life-time assessment of DSM-IV pathological gambling symptoms). Polygenic scores for neuroticism interact with age to suggest that the positive association becomes stronger from adolescence through young adulthood.

Effects of genetic risk for alcohol dependence and onset of regular drinking on the progression to alcohol dependence: A polygenic risk score approach.

BACKGROUND: Prior studies have established the importance of genetic contributions to the etiology of alcohol dependence (AD), and suggested an early onset of alcohol use represents an initial marker of this genetic risk, which is associated with a more rapid progression to AD and increased risk for AD itself. Building on prior work, the current study examined whether the additive effects of AD risk variants predicted the rate of progression to AD from the onset of regular drinking, a drinking milestone with high clinical relevance to AD prevention. METHODS: Data from 1501 European-ancestry adults from the University of California - San Francisco Family Alcoholism Study were used to examine whether polygenic risk scores for AD (PRSAD) and age-at-onset of regular drinking contributed uniquely to the likelihood of having a lifetime AD diagnosis and the rate of progression from regular drinking to AD. Mixed effects logistic regression and Cox proportional hazards regression analyses were employed. RESULTS: Increases in PRSAD were associated with a faster progression from regular drinking to AD independent of age-at-onset of regular drinking. An independent effect of age-at-onset of regular drinking was also observed indicating that a one-year delay in regular drinking was associated with a 7% decrease in the hazard of progression to AD among drinkers with an early onset (≤ 18), but a 3% increase among drinkers with a late onset (> 18) of regular drinking. CONCLUSIONS: These results broaden our understanding of the contributions of measured genotypes underlying AD-risk on the etiology and clinical course of AD.

The Association Between Alcohol Consumption and Pain Interference in a Nationally Representative Sample: The Moderating Roles of Gender and Alcohol Use Disorder Symptomatology.

BACKGROUND: Prior research on alcohol consumption and pain has yielded inconsistent results regarding the directionality of effects for both consumption-to-pain and pain-to-consumption relations. The present study sought to examine directionality of these relations by testing bidirectional longitudinal associations between consumption and pain interference, a crucial aspect of pain that captures pain-related disability and has been regarded as a valuable measure of treatment outcome. In addition, this study explored possible moderation of these bidirectional longitudinal associations by gender and alcohol use disorder (AUD) symptomatology. METHODS: Analyses included 29,989 current/former drinkers who were interviewed at both waves (2001 and 2004) of the U.S. National Epidemiological Survey on Alcohol and Related Conditions (NESARC). Analyses used self-report data from both waves on past-year average daily volume of alcohol consumed and past-month pain interference (1 item from the Medical Outcomes Study 12-item Short-Form Health Survey [MOS-SF-12]). AUDADIS-IV data from Wave 1 were used to index baseline AUD symptomatology (i.e., symptom count). Cross-lagged panel modeling and multigroup analyses were employed. RESULTS: Regarding the consumption-to-pain-interference relation, in general, higher baseline alcohol consumption was associated with lower subsequent pain interference at follow-up. However, among men with higher AUD-symptom counts, the opposite pattern emerged, with higher baseline alcohol consumption being significantly related to higher subsequent pain interference at follow-up. Regarding the pain-interference-to-consumption relation, higher baseline pain interference was significantly associated with lower subsequent alcohol consumption at follow-up, and no moderating effects were observed. CONCLUSIONS: The distinctive patterns of the consumption-to-pain-interference relation observed among men with elevated AUD symptomatology suggest that this relation might be driven by different mechanisms across different groups of individuals. Specifically, the detrimental effect of alcohol on pain interference might emerge at relatively advanced stages of AUD among men, consistent with Koob's Dark Side of Alcohol Addiction theory in human research.

Effects of Common and Rare Chromosome 4 GABAergic Gene Variation on Alcohol Use and Antisocial Behavior.

OBJECTIVE: Epidemiological estimates suggest that nearly half of individuals diagnosed with alcohol use disorder will be diagnosed with another mental health disorder, with strong associations involving other externalizing disorders. Molecular genetic studies investigating the relation between alcohol use disorder and externalizing behaviors (e.g., antisocial behavior) have focused on a cluster of chromosome 4 γ-aminobutyric acid (GABA) receptor genes (GABRG1-A2-A4-B1) but have generated varying results. METHOD: The current study examined associations between common and rare variation in this region with alcohol use disorder and antisocial behavior using genetic sequencing data. Specifically, the University of California at San Francisco Family Alcoholism Sample (n = 1,610; 62% female) was used to conduct common and rare variant association tests in the GABRG1-A2-A4-B1 cluster with DSM-5 alcohol use disorder symptom counts, antisocial behavior, and a product term representing their interaction. RESULTS: Gene-based analyses of rare variation resulted in a significant association between rare GABRA2 variation and the interaction term. Single-variant analysis yielded only nominally significant associations. The strongest association for alcohol use disorder (rs3756007) was located in GABRA2, the strongest association for antisocial behavior (rs11941860) was located in GABRG1, and the interaction term yielded top associations in GABRA2 (rs2119183) and the intergenic region between GABRA2 and GABRG1 (rs536599). Common and rare variant associations for the interaction remained similar when covarying for the effects of the other type of variation, suggesting that the significant rare variant signal is independent of common variant contributions. CONCLUSIONS: The present study suggests that both rare and common variant associations in GABRA2 confer risk for alcohol use disorder and antisocial behaviors, indicating a potential liability toward externalizing behavior more broadly.

Differential item functioning analysis of the CUDIT and relations with alcohol and tobacco use among men across five ethnic groups: The HELIUS study.

Cannabis use has been rising despite recognition of the negative consequences associated with heavy use. The severity of these consequences has been shown to differ across racial/ethnic groups, even when controlling for consumption levels. The present study conducted an item response theory (IRT) analysis of the Cannabis Use Disorders Identification Test (CUDIT) to better understand the patterns of problematic cannabis use and their relation with other substance use across ethnic groups in the Healthy Life in an Urban Setting (HELIUS) study. CUDIT responses from 1,960 cannabis-using African Surinamese, South-Asian Surinamese, Dutch, Moroccan, and Turkish ethnic origin participants were used to test for differential item functioning (DIF) within an IRT framework. After restricting the sample to men because of low frequency of use among women, several instances of uniform DIF were identified. Multiple-group IRT analysis yielded a harmonized cannabis use phenotype that was used to estimate ethnic group differences in problematic cannabis use and its relation to alcohol and tobacco co-use. These analyses suggested that cannabis users from certain ethnic minority groups experienced higher rates of problematic use than the majority group despite lower rates of cannabis use. Further, cannabis and tobacco use were positively related across groups, whereas only ethnic minority groups showed a positive relation between cannabis and alcohol use. These results demonstrate the importance of accounting for DIF when examining group differences in problematic cannabis use, and support prior evidence suggesting that certain ethnic minority groups may be more likely to experience problematic cannabis use and alcohol co-use relative to the majority group. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Polygenic Risk Scores for Psychiatric Disorders Reveal Novel Clues About the Genetics of Disordered Gambling.

Disordered gambling (DG) is a rare but serious condition that results in considerable financial and interpersonal harms. Twin studies indicate that DG is heritable but are silent with respect to specific genes or pathways involved. Existing genomewide association studies (GWAS) of DG have been substantially underpowered. Larger GWAS of other psychiatric disorders now permit calculation of polygenic risk scores (PRSs) that reflect the aggregated effects of common genetic variants contributing risk for the target condition. The current study investigated whether gambling and DG are associated with PRSs for four psychiatric conditions found to be comorbid with DG in epidemiologic surveys: major depressive disorder (MDD), attention-deficit hyperactivity disorder (ADHD), bipolar disorder (BD) and schizophrenia (SCZ). Genotype data and survey responses were analyzed from the Wave IV assessment (conducted in 2008) of the National Longitudinal Study of Adolescent to Adult Health, a representative sample of adolescents recruited in 1994-1995 and followed into adulthood. Among participants classified as having European ancestry based on genetic analysis (N = 5215), 78.4% reported ever having gambled, and 1.3% reported lifetime DG. Polygenic risk for BD was associated with decreased odds of lifetime gambling, OR = 0.93 [0.87, 0.99], p = .045, pseudo-R2(%) = .12. The SCZ PRS was associated with increased odds of DG, OR = 1.54 [1.07, 2.21], p = .02, pseudo-R2(%) = .85. Polygenic risk scores for MDD and ADHD were not related to either gambling outcome. Investigating features common to both SCZ and DG might generate valuable clues about the genetically influenced liabilities to DG.

Polygenic liability for schizophrenia predicts shifting-specific executive function deficits and tobacco use in a moderate drinking community sample.

Individuals with schizophrenia have higher lifetime rates of substance use disorders than the general population, and research suggests high comorbidity rates may be partially explained by shared genetic influences related to common underlying etiology. Moreover, deficits in executive functions are thought to be central to the diagnosis of schizophrenia and are likewise associated with alcohol and tobacco use. The current study examined the associations between schizophrenia polygenic risk scores and tobacco and alcohol use and the mediation of these associations by executive function sub-domains. Results from the Psychiatric Genomics Consortium's meta-analysis of genome-wide association studies of schizophrenia were used to calculate polygenic risk scores in a sample of moderate drinkers. Schizophrenia risk scores were significantly associated with shifting-specific executive function deficits and tobacco use phenotypes. However, risk scores were not significantly associated with alcohol use and executive functions were not significantly associated with either tobacco or alcohol use. These findings extend previous research by suggesting that genetic risk for schizophrenia may be associated with specific sub-domains of executive function as well as smoking. The lack of a relation with alcohol use suggests genetic factors related to schizophrenia and executive functioning may not influence drinking in a non-disordered, social-drinking sample.

Genetic loci for alcohol-related life events and substance-induced affective symptoms: indexing the "dark side" of addiction.

A limited number of genetic variants have been identified in traditional GWAS as risk or protective factors for alcohol use disorders (AUD) and related phenotypes. We herein report whole-genome association and rare-variant analyses on AUD traits in American Indians (AI) and European Americans (EA). We evaluated 742 AIs and 1711 EAs using low-coverage whole-genome sequencing. Phenotypes included: (1) a metric based on the occurrence of 36 alcohol-related life events that reflect AUD severity; (2) two alcohol-induced affective symptoms that accompany severe AUDs. We identified two new loci for alcohol-related life events with converging evidence from both cohorts: rare variants of K2P channel gene KCNK2, and rare missense and splice-site variants in pro-inflammatory mediator gene PDE4C. A NAF1-FSTL5 intergenic variant and an FSTL5 variant were respectively associated with alcohol-related life events in AI and EA. PRKG2 of serine/threonine protein kinase family, and rare variants in interleukin subunit gene EBI3 (IL-27B) were uniquely associated with alcohol-induced affective symptoms in AI. LncRNA LINC02347 on 12q24.32 was uniquely associated with alcohol-induced depression in EA. The top GWAS findings were primarily rare/low-frequency variants in AI, and common variants in EA. Adrenal gland was the most enriched in tissue-specific gene expression analysis for alcohol-related life events, and nucleus accumbens was the most enriched for alcohol-induced affective states in AI. Prefrontal cortex was the most enriched in EA for both traits. These studies suggest that whole-genome sequencing can identify novel, especially uncommon, variants associated with severe AUD phenotypes although the findings may be population specific.